| BackgroundThe increasing use of contrast agent for imaging in diagnostic and interventional procedures, especially during coronary angiography, has raised wide concerns about the increasing incidence of a potential complication known as contrast-induced nephropathy (CIN). It is generally defined as an impairment in the renal function with an increase in serum creatinine (SCr) by0.5mg/dL(44.8μmol/L) or25%from the baseline, occurring within3days of exposure to intravascular contrast medium in the absence of an alternative etiology. Symptoms occur48-72hours after contrast medium exposure, with creatinine peaking3-5days later and normalizing within7days in most cases.The incidence of CIN varies widely from study to study due to the differences in the definition of CIN, baseline renal dysfunction, type of contrast media and the dose of contrast media used in each study. In patients undergoing the same procedure without evidence of pre existing renal insufficiency, the risk of developing a significant reduction in renal function is0%to0.5%. In patients undergoing coronary angiography with pre existing renal impairment, the incidence of worsening renal function is10-40%. While in patients with pre existing renal impairment and diabetes, the incidence of CIN may up to50%. Other risk factors include congestive cardiac failure, age over70years, dehydration, and concurrent administration of nephrotoxic drugs. CIN is the third most common cause of hospital-acquired kidney failure, it is associated with adverse clinical outcomes, prolongation of hospitalization, increased medical care costs and increased risk of death. The pathophysiology of contrast-induced nephropathy are not well understood. It is hypothesized that renal vasoconstriction leading to renal medullary ischemia and a direct toxic effect of contrast agent on tubular epithelial cells may cause CIN. Initially, there is a transient vasodilation and increase in renal blood flow followed by vasoconstriction and a reduction in renal blood flow, which is proportional to the osmolality of the injected substance, while renal ischemia will induce the generation of oxygen free radicals and oxidative stress. In addition, the viscosity and high permeability of the contrast agent will decrease renal blood flow and generate the renal vascular thrombosis, deteriorating the renal function.Many studies have looked at the use of different treatment modalities to reduce the incidence or level of renal impairment incurred. Only periprocedural hydration, minimization of the volume of contrast agent and careful utilization of nephrotoxic drugs have been shown to be protective. Studies with other treatment, such as hemofiltration, fenoldopam, furosemide, dopamine, mannitol, calcium channel blockers, and atrial natriuretic peptide, have shown mixed results, requiring larger studies to further confirm.N-acetylcysteine (NAC) is a direct scavenger of free radicals, it is also a precursor for the synthesis of glutathione (GSH), which is a powerful antioxidant with activity against free radicals. NAC can improve blood flow through stabilizing nitric oxide. NAC possesses both vasodilatory and antioxidative properties, which are thought to provide protection against CIN. However, pharmacokinetic studies have confirmed that the bioavailability of oral NAC is low, ranging from4%to10%, mainly due to the first-pass hepatic metabolism, suggests that only a small proportion of the administered dose is available for renal protection. Due to the substantially different pharmacokinetic and pharmacodynamic profiles between intravenous and oral NAC, it has been suggested that the intravenous form of NAC may be more effective in preventing CIN. However, a few studies focused on intravenous NAC therapy as specific prophylactic measures of contrast-induced nephropathy have been published with mixed results, a few studies demonstrated a reduction in incidence of CIN while others reported a no significant benefit. Up to now, there is no meta-analysis designed to evaluate the efficacy of intravenous NAC for the prevention of CIN.Objective:We performed a meta-analysis of the randomized controlled trials (RCTs) in order to assess the efficacy and safety of intravenous NAC for the prevention of contrast-induced nephropathy and to provide a basis for clinical practice.Methods1. Inclusion and exclusion criteria were set according to Cochrane guidelines, including the characteristics of the subjects, interventions and outcomes.2. Potential randomized, controlled trials published up to September2012that evaluated the efficacy of intravenous N-acetylcysteine for preventing CIN were from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials. We also manually searched the conference proceedings of major cardiology and nephrology meetings and reference lists from eligible trials. The primary outcome was contrast-induced nephropathy. Secondary outcomes including length of hospital stay, in-hospital mortality and the requirement for renal replacement therapy.3. To assess the quality of qualified studies, two reviewer independently using a predetermined quality assessment tool including similarity of study groups at baseline, eligibility/exclusion criteria, methods of allocation concealment, using of a placebo, use of any blinding procedure, intention-to-treat analysis and dropouts,.4. Two reviewers independently reviewed the studies identified by the predetermined search strategies to determine whether the study met the inclusion and exclusion criteria and perform data extraction using standardized data collection forms. The following information was extracted from each study:patient characteristics (average age, percentage of men, baseline serum creatinine, and percentage of diabetic patients), type of angiographic or radiologic imaging, inclusion and exclusion criteria, type of contrast agent used and dose, hydration regimen, precise definition of contrast-induced nephropathy, dosage and timing of N-acetylcysteine. Data from the selected RCTs were combined to estimate the summary relative risk (RR) with95%confidence intervals (CIs) using a random-effects model as described by Der Simonian and Laird. We assessed the presence of publication bias using both a funnel plot and an Egger’s weighted regression test. We also performed Meta-regression analyses to isolate potential sources of heterogeneity.Results1. Study and patient characteristics:Ten trials fulfilled our inclusion criteria were included in final analysis. The total number of patients included was1916, of which962patients were randomized to NAC groups and954randomized to control groups. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The definition of CIN varied widely across studies. All patients in included studies were received a hydration protocol around their procedure and all received low or iso-osmolar non-ionic contrast agent, but the total amount of NS given was not consistently reported and the dose of contrast agent varied widely. The lowest mean dose of contrast agent reported was120ml, while the highest mean dose was230ml. The baseline characteristics were well-balanced in each individual trial2. Results of meta-analysis2.1primary outcome (Contrast-induced Nephropathy)The incidence of Contrast-induced Nephropathy in the ten trails varied widely. The incidence of CIN in the control group ranged from5.9%to23.8%with an average of14.3%. The incidence of CIN in the treatment group ranged from2.5%to16.0%with an average of7.9%. Three studies found the incidence of CIN was significant lower in NAC recipients compare with control group, whereas seven studies found no significant difference. The summary risk ratio (RR) of CIN by random effects approach was0.68(95%CI,0.45-1.02, P=0.06), indicating a borderline significant trend towards benefit among NAC recipients. However, there was evidence of significant heterogeneitybetween studies in the relative risk of CIN with NAC therapy.(I2=48%; Q=17.42, P=0.04). So the RR should be interpreted with caution.2.2Sensitivity analysesSeveral sensitivity analyses were performed. Firstly, Analyses were repeated in those trials involving cardiac catheterization or peripheral angiography (all studies except Poletti et al.). The summary risk ratio for CIN associated with the use of NAC was essentially unchanged at0.72(95%CI,0.47-1.09, P=0.12), and substantial heterogeneity remained (.P=0.03). Secondly, the study by Webb et al, which used a extremely lower dose intravenous acetylcysteine compared with other studies, were excluded from our analysis.The overall effect of NAC on CIN demonstrated statisticallysignificant (RR=0.59;95%CI,0.36-0.97, P=0.04). However, significant heterogeneity was still presented (P=0.03).Finally, when only the studies with a measured Jadad ’score of3or more were combined, heterogeneity was reduced (chi-squared test of heterogeneity, P=0.23), and the overall effect of intravenous NAC on CIN demonstrated statistically nonsignificant (RR0.77,95%CI,0.50-1.15, P=0.20).2.3Meta-regressionTo assess the possibility that identifiable differences between studies accounted for the heterogeneity, we performed meta-regression by random effects approach examining one covariate at a time. Meta-regression analyses demonstrated that the study size may partially explained the heterogeneity with a nonnegative coefficient (coefficient=0.98, P=0.08). No significant relationships between the effect of NAC on CIN and baseline serum creatinine (coefficient=-1.02, P=0.16), contrast volume (coefficient=-0.08, P=0.92) or proportion of diabetes mellitus (coefficient=-0.01, P=0.83). Similarly, heterogeneity was not accounted for intention to treat analysis (coefficient=-0.42, P=0.30), allocation concealment (coefficient=0.73, P=0.17), double-blinding (coefficient=0.66, P=0.17), or Jadad’s score (coefficient=0.13, P=0.59).2.4Publication bias The funnel plot of the SE of the log RR versus the log RR showed asymmetry, suggesting the paucity of small negative studies in the lower right of the funnel plot, which was confirmed by Egger’s test (P=0.013).2.5Secondary outcomes (Renal failure requiring dialysis, Mortality, Length of hospitalization)The incidence of actue renal failure requiring dialysis was very low. In total,7patients required dialysis, among whom four received acetylcysteine and three were in control groups. The summary relative risk of actue renal failure requiring dialysis was0.72(95%CI,0.34to4.75, P=0.72). There was no significant heterogeneity (P=0.32). The information on in-hospital mortality was reported in4studies. The summary risk ratio of in-hospital mortality with intravenous NAC in the four trials was0.67(95%CI,0.32-1.40, P=0.29). There was no significant heterogeneity (P=0.99). Carbonell et al. also provided information on1-year mortality, however, there was no significant difference in mortality in NAC group compare to control group (15.4%vs.21.4%, P=0.67). Date on the length of hospital stay was available from three trials. However, none of the three trials reported a significant reduction in hospital stay in NAC group, and data required to be pooled was not sufficient.2.6Adverse eventsOf the10trials, only Baker et al found a higher rate of tetter, flushing and itching. However, these events were easily and safely treated by discontinuation of NAC infusion and administering antihistamine.ConclusionsThis meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for intravenous NAC in CIN prevention. |
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